Multiple drug delivery from a balloon and a prosthesis

ABSTRACT

System for treating vascular disease comprising a balloon having an outer surface for temporary contact with a vessel wall when in an expanded state, a coating disposed on at least a portion of the outer surface, the coating including an initial amount of a cytostatic agent selected from the group consisting of Zotarolimus (ABT578), everolimus, pimecrolimus, and a combination thereof, the coating being capable of maintaining a therapeutically effective amount of the cytostatic agent on the outer surface for delivery to a vessel wall, and further wherein between about 4.9% to about 23% of the initial amount of the cytostatic agent on the outer surface remains disposed on the outer surface after delivery of the therapeutically effective amount of the cytostatic agent to the vessel wall, and optionally, a stent disposed on the balloon.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/935,025, filed on Jul. 3, 2013, which is a continuation ofU.S. patent application Ser. No. 13/617,628, filed on Sep. 14, 2012, nowU.S. Pat. No. 8,501,213, which is a continuation of Ser. No. 12/371,422,filed on Feb. 13, 2009, now U.S. Pat. No. 8,431,145, which is acontinuation-in-part of U.S. patent application Ser. No. 11/084,172,filed on Mar. 18, 2005, now U.S. Pat. No. 8,057,813, which claimspriority from U.S. Provisional Application No. 60/554,730, filed on Mar.19, 2004, each of which is hereby incorporated in their entirety byreference.

BACKGROUND OF THE INVENTION

1. Related Application

The present invention relates to an interventional device for deliveryof therapeutic agents from an angioplasty balloon and from a prosthesissuch as an intraluminal stent. The invention also relates to the methodof loading the beneficial agents onto the balloon and the medicaldevice, as well as the method of delivery of the agents from separatesurfaces. The invention also relates to an interventional device havinga prosthesis surface that is loaded with a first beneficial agent, and aballoon surface loaded with a second beneficial agent. The inventionalso relates to a method of loading multiple beneficial agents onto theprosthesis surfaces and the balloon surfaces, and to a method ofmanufacturing an interventional device for the delivery of a firstbeneficial agent and a second beneficial agent from separate surfaces.

2. Description of Related Art

Balloon angioplasty associated with the implantation of a vascular stentis a procedure designed to expand occluded blood vessels, resulting inadequate perfusion of distal tissues. The stent, which is crimped ontothe balloon, is introduced via a peripheral artery, and advanced to thelesion site over a guidewire. Inflation of the balloon results incompression of plaque and simultaneous implantation of the stent, whichacts as a scaffold to keep the vessel expanded to its normal diameter.The balloon is then deflated, allowing removal of the catheter assembly,leaving the stent in place to maintain patency of the vessel.

This percutaneous intervention, described as PCI when associated withcoronary balloon angioplasty, has been effective in normalizing thevessel lumen, and providing relief of pain often associated withmyocardial ischemia. The procedure is not restricted to the coronaryvasculature, but may also be applied to other vessels, including renal,carotid, iliac and superficial femoral arteries. However, although thesuccess of the intervention is generally high, the long-term patency ofthe vessel is often reduced by restenosis of the vessel at the site ofthe original lesion. This restenotic process is the consequence of avariety of factors acting in concert to re-occlude the vessel, reducingblood flow and nutrient supply to tissues. These include progression ofthe underlying disease, as well as the generation of cytokines and othergrowth factors which promote cell proliferation. These factors emanatefrom a variety of inflammatory cell types including monocytes andmacrophages. In addition to inflammation and cell proliferation,migration of cells from the medial or adventitial layers of the vesselwall may contribute to the growth of a new layer, described asneointima, which re-occludes the vessel. In recent years, the use ofbare metal stents, while effective in the short-term, has beenassociated with a significant rate of restenosis. Therefore, manyinvestigators have sought to provide technologies to reduce therestenosis rate, while maintaining the beneficial effects offered bythese metal scaffolds. The coating of stents with bioinert polymers hasbeen somewhat effective, but the most important advance in this fieldhas been the loading of these polymers with drugs known to block cellproliferation One commonly applied technique for the local delivery of adrug is through the use of a polymeric carrier coated onto the surfaceof a stent, as disclosed in Berg et al., U.S. Pat. No. 5,464,650, thedisclosure of which is incorporated herein by reference. Suchconventional methods and products generally have been consideredsatisfactory for their intended purpose. The gradual elution of drugfrom the polymer is known to impact the restenotic process, providingbeneficial concentrations of the beneficial agent at a time when theinflammatory and proliferative processes are thought to be mostprevalent. The introduction of these drug-eluting stents (DES) hasreduced the restenosis rate from 20-30% to less than 10% in severalclinical trials. However, many are attempting to reduce the rate evenfurther, providing nearly all patients who receive a DES with long-termvessel patency and minimal chance of return to the cath lab for repeatprocedures. The delivery of multiple drugs, using both the stent and theballoon itself as delivery platforms, may help to achieve this goal.

As evident from the related art, conventional methods of loadinginterventional devices with beneficial agents, such as drugs, oftenrequires coating the entire prosthesis with a polymer capable ofreleasing beneficial drugs, as disclosed in Campbell, U.S. Pat. No.5,649,977 and Dinh et al., U.S. Pat. No. 5,591,227, the disclosures ofwhich are incorporated by reference.

Therefore, the present invention proposes the use of one or morebeneficial agents, applied to the surface of the balloon material by anymethod, and the application of one or more beneficial agents applied toeither the bare-metal surface of a second device, or incorporated withthe polymer which coats the second device. The delivery of thebeneficial agent from the balloon is expected to occur during eitherpre-dilatation of the vessel at the lesion site, or from the balloonduring the delivery of the device during a stenting procedure.Additionally, the delivery of the beneficial agent can be from theballoon during a final stent sizing balloon expansion. The delivery ofthe beneficial agent from the prosthesis is expected to occur over alonger period, as the drug is released from the polymer or from thesurface of the device. The associated prosthesis may be placed directlywhen the balloon is inflated at the lesion site, immediately after ascommonly practiced in pre-dilatation procedures, or within a suitabletime period in a second interventional procedure.

SUMMARY OF THE INVENTION

The purpose and advantages of the present invention will be set forth inand apparent from the description that follows, as well as will belearned by practice of the invention.

Additional advantages of the invention will be realized and attained bythe methods and systems particularly pointed out in the writtendescription and claims hereof, as well as from the appended drawings.

According to one embodiment, the present invention relates to a systemfor delivering a beneficial agent. The system includes a balloon havinga coating loaded with a beneficial agent (such as a drug) and aprosthesis having a coating loaded with a beneficial agent (which canalso be a drug that is the same or different than the beneficial agenton the balloon.) The balloon and the prosthesis can have more than onebeneficial agent in the respective coatings. The coatings can becontinuous over the surface of the balloon or the prosthesis ordiscontinuous. Numerous beneficial agents are suitable for deliveryaccording to the invention.

According to another embodiment, the present invention relates tomethods of treating and preventing a vascular disease. The inventivemethods include delivery of a balloon having a coating loaded with abeneficial agent and delivery of a prosthesis having a coating loadedwith a beneficial agent. The delivery of the balloon and the prosthesisto a target site can be sequential or simultaneous. The coatedprosthesis can be delivered before or after the coated balloon. Thebeneficial agents delivered from the balloon can be the same as ordifferent from those delivered from the stent.

According to other embodiments, the present invention relates to amethod of providing a device for treatment and prevention of vasculardisease, including techniques for coating the balloon with beneficialagents.

To achieve these and other advantages and in accordance with the purposeof the invention, as embodied and broadly described, the inventionincludes an interventional device for the delivery of multiplebeneficial agents wherein the device comprises a prosthesis to bedeployed in a lumen, the prosthesis having a surface; a first beneficialagent loaded on the surface of the prosthesis; and a balloon to expandthe prosthesis; and a second beneficial agent loaded on the surface ofthe balloon.

In a further aspect of the invention, the first beneficial agent and thesecond beneficial agent can be incompatible with each other ordetrimental to each other. The first beneficial agent can be dissolvedin a first solvent and the second beneficial agent can be dissolved in asecond solvent, wherein the first solvent and the second solvent areimmiscible. Similarly, the first beneficial agent can react with thesecond beneficial agent. It is possible for the first beneficial agentto be more hydrophobic than the second beneficial agent. Also, the firstbeneficial agent can be loaded along a first controlled trajectory onthe prosthesis and the second beneficial agent can be loaded along asecond controlled trajectory on the balloon.

In a further aspect of the invention, an interventional device isprovided wherein at least one of the first beneficial agent and thesecond beneficial agent is mixed with a binder prior to being loaded onthe prosthesis or the balloon.

In accordance with another aspect of the invention, an interventionaldevice is provided wherein the first beneficial agent is mixed with abinder having a first release rate for delivery of the first beneficialagent from the prosthesis. The second beneficial agent can be mixed witha binder having a second release rate for delivery of the secondbeneficial agent from the balloon; the first release rate beingdifferent than the second release rate. The first beneficial agent canbe different than the second beneficial agent.

In accordance with another aspect of the invention, an interventionaldevice is provided wherein the first beneficial agent has a first localareal density and the second beneficial agent has a second local arealdensity. At least one of the first local areal density and the secondlocal areal density can be uniform across a selected portion of theprosthesis or balloon. Also, at least one of the first local arealdensity of beneficial agent and the second local areal density can bevaried across a selected portion of the prosthesis or balloon. The firstlocal areal density of the first beneficial agent can be different thanthe second local areal density of the second beneficial agent. Theinterventional device can further include a third beneficial agentloaded on at least one of the first surface and second surface of theprosthesis or on the balloon.

In accordance with still another aspect of the invention, aninterventional device is provided wherein the prosthesis furtherincludes a layer of base material on a selected portion thereof, and thefirst beneficial agent is loaded to the base material layer. The basematerial layer defines a pattern for loading the first beneficial agent.This prosthesis is then combined with a balloon that is coated with asecond beneficial agent.

In accordance with a further aspect of the invention, the prosthesisincludes at least one cavity defined therein. The cavity can be filledwith multiple beneficial agents. Preferably, the at least one cavity isat least partially loaded with a base material, and multiple beneficialagents are loaded to the base material. This prosthesis is then combinedwith a balloon that is coated with a second beneficial agent.

The invention also provides a method of loading multiple beneficialagents onto a prosthesis for delivery within a lumen wherein the methodcomprises the steps of providing a prosthesis to be deployed within alumen; providing a first beneficial agent and to be loaded on theprosthesis; providing an additional beneficial agent to be loaded on theprosthesis. This prosthesis is then combined with a balloon that iscoated with a second beneficial agent.

In accordance with a further aspect of the invention, the firstbeneficial agent provided by the first beneficial agent providing stepis incompatible with the second beneficial agent provided by the secondbeneficial agent providing step. The first beneficial agent provided bythe first beneficial agent providing step can be dissolved in a firstsolvent and the second beneficial agent provided by the secondbeneficial agent providing step can be dissolved in a second solvent.The first solvent and the second solvent can be immiscible. The firstbeneficial agent provided by the first beneficial agent providing stepalso can be reactive with the second beneficial agent provided by thesecond beneficial agent providing step. Furthermore, the dispensingsteps can be performed to define an interspersed pattern of the firstbeneficial agent on the prosthesis and the second beneficial agent onthe balloon, if desired. The dispensing steps are performedsimultaneously. The dispensing steps also can be performed to define anoverlapping pattern of the first beneficial agent and the secondbeneficial agent.

In accordance with another aspect of the invention, the method canfurther include the step of mixing the first beneficial agent with abinder prior to the first beneficial agent dispensing step onto theprosthesis and a step of mixing the second beneficial agent with abinder prior to the second beneficial agent dispensing step onto theballoon. In accordance with a still further aspect of the invention, themethod can further include the step of mixing the first beneficial agentwith a first binder having a first release rate for delivery of thefirst beneficial agent from the prosthesis and the second beneficialagent with a second binder having a second release rate for delivery ofthe second beneficial agent from the balloon. The first release rate canbe different than the second release rate, and first beneficial agentcan be different than the second beneficial agent.

In accordance with another aspect of the invention, a method is providedwherein the first beneficial agent dispensing step is performed toprovide the first beneficial agent with a first local areal density andthe second beneficial agent dispensing step is performed to provide thesecond beneficial agent with a second local areal density, wherein atleast one of the first local areal density and the second local arealdensity is varied across a selected portion of the prosthesis orballoon.

In accordance with still another aspect of the invention, a method canbe provided further including the step of applying a layer of basematerial on a selected portion of the prosthesis, and the dispensingsteps are performed to introduce the first beneficial agent to the basematerial layer. The base material layer can be applied to define apattern for loading the first beneficial agent. This prosthesis is thencombined with a balloon that is coated with a second beneficial agent.

The invention also includes an interventional device for delivery ofbeneficial agent, where the beneficial agent can be selected from agroup consisting of antithrombotics, anticoagulants, antiplateletagents, anti-lipid agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, smooth muscle cellinhibitors, antibiotics, growth factor inhibitors, cell adhesioninhibitors, cell adhesion promoters, antimitotics, antifibrins,antioxidants, antineoplastics, agents that promote endothelial cellrecovery, antiallergic substances, radiopaque agents, viral vectors,antisense compounds, oligionucleotides, cell permeation enhancers,angiogenesis agents, and combinations thereof. The prosthesis can be astent, graft, or stent-graft. The prosthesis may also be a vascular orbiliary stent or an embolic capture device. The interventional devicecan include an overcoat applied to at least one of the inner surface orthe outer surface of the prosthesis. The prosthesis coating or ballooncoating can be applied by dip coating, spray coating, or ink jettingwhere the fluid-dispenser can be a drop-on-demand fluid type printer ora charge-and-deflect type print head. Additionally, the beneficial agentcan be built up on the prosthesis or balloon by applying multiplelayers. Furthermore, the beneficial agent can be mixed with a binder andalso can be loaded onto the prosthesis with a polymer. The polymer ispreferably biocompatible. For example, the polymer can be amacromolecule containing pendant phosphorylcholine groups such aspoly(MPC_(w):LMA_(x):HPMA_(y):TSMA_(z)), where MPC is 2methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate. The binder can be composed of complex sugars (mannitol),starches (e.g., cellulose), collagens. In general the binder would benoncrystalline, have low water solubility, have good film formingcharacteristics, good solubility with solvents that may be used todissolve the drug, biocompatible, inert (nonreactive with respect to thedrug and also body tissues, fluids, etc), polymer, (e.g., hydrogel), canbe hydrophobic if not hydrogel, especially if it is not permanentlyattached to balloon (if permanently attached, then can use hydrogel, canbe used to absorb drug and then when balloon inflated, will squeeze outthe drug into ablumenal tissue), low blood solubility if not permanentlyattached to balloon

In accordance with another aspect of the invention, the beneficialagents can be applied to the interventional device using a fluid jetdispenser capable of dispensing discrete droplets along a controlledtrajectory, such as drop-on-demand fluid type printer or acharge-and-deflect type printer. In accordance with a further aspect ofthe invention, the beneficial agent can be mixed with a binder. Thebeneficial agent preferably is loaded onto the prosthesis with apolymer. Preferably, the polymer is a phosphorylcholine material. Thesecond beneficial agent preferably is loaded onto the balloon with anonpolymer film forming excipent.

In yet another aspect of the invention, the prosthesis has a tubularbody when deployed, wherein the tubular body defines a longitudinalaxis. The first surface of the prosthesis is defined as an inner surfaceof the tubular body, and the second surface of the prosthesis is definedas an outer surface of the tubular body.

In yet another aspect of the invention, the balloon is loaded with thesecond beneficial agent such that the delivery of the second agentextends beyond the proximal and distal ends of the prosthesis.

In yet another aspect of the invention, the balloon is loaded with thesecond beneficial agent such that the delivery of the second agent isdelivered in a burst fashion to delivery high drug concentration locallyto the tissue very rapidly, whereas the beneficial agent delivered fromthe prosthesis may be delivered over a longer time frame.

In further accordance with the invention, the first surface is loadedwith beneficial agent selected from a group consisting of antiplateletagents, aspirin, cell adhesion promoters, agents that promoteendothelial healing, agents that promote migration and estradiol. Thesecond beneficial agent can be selected from a group consisting ofanti-inflammatories, anti-proliferatives, smooth muscle inhibitors, celladhesion promoters, and the rapamycin analog, ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.

In accordance with another aspect of the invention, an interventionaldevice is provided wherein the first surface of the prosthesis isdefined by a plurality of interconnecting structural members andprosthesis includes a first selected set of the structural members andthe second surface of the prosthesis includes a second selected set ofthe structural members. At least one of the first selected set ofstructural members and the second selected set of structural members candefine at least one ring-shaped element extending around a circumferenceof the tubular body.

The invention also provides a method of manufacturing an interventionaldevice for the delivery of beneficial agent where the method comprisesthe steps of providing a prosthesis to be deployed in a lumen, theprosthesis having a first surface and a second surface; providing afirst beneficial agent to be delivered from the prosthesis; providing asecond beneficial agent to be delivered from the balloon; loading thefirst beneficial agent to at least a portion of the first surface of theprosthesis; and loading the second beneficial agent to at least aportion of the balloon.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and are intended toprovide further explanation of the invention claimed.

The accompanying Figures, which are incorporated in and constitute partof this specification, are included to illustrate and provide a furtherunderstanding of the method and system of the invention. Together withthe description, the Figures serve to explain the principles of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of an angioplasty procedure andstent placement equipment showing a balloon on a catheter and thesyringe systems used to inflate the balloon.

FIG. 2A is a schematic representation of a stent crimped onto a catheterballoon. FIG. 2B shows a blowup of the balloon and stents section of thecatheter with the shading on the balloon representing a coating of asecond beneficial agent and the shading of the stent struts representinga coating of a first beneficial agent.

FIG. 3 is a schematic representation of an embodiment of the system ofthe present invention showing a cross section through a stent crimpedonto a catheter balloon. The dark center is the catheter body, the whiteis the balloon, the squares are the individual struts of the stent, theshading on the balloon representing a coating of a second beneficialagent on the balloon and the shading of the stent struts representing acoating of a first beneficial agent on the stent.

FIGS. 4A-C each depict a schematic representation of the embodiment ofthe system of the present invention for the delivery of the beneficialagents to a vessel wall and collectively depict the process ofdelivering a stent from a balloon to expand the lumen of a narrowedvessel, wherein FIG. 4A shows the placement of the balloon-stentcombination at the site of delivery, FIG. 4B shows the expansion of theballoon, which results in the expansion of the stent against the vesselwall, and FIG. 4C shows the result after the balloon is deflated andremoved leaving the stent behind.

FIG. 5A depicts a schematic representation of a prosthesis or balloonloaded with beneficial agent having a first portion and a second portionhaving different local areal densities of beneficial agent in accordancewith the present invention, and FIGS. 5B and 5C each depict a graphdemonstrating corresponding areal density.

FIG. 6A is a schematic representation of a balloon catheter, and FIG. 6Bshows a blowup of the balloon catheter with the shading on the balloonrepresenting a coating of a beneficial agent.

FIG. 7 depicts a graph illustrating the comparative results ofsemi-quantitative angiographic scoring (narrowed compared to referencediameter score >1) of P (TriMaxx Stent on uncoated balloon), DEB(TriMaxx Stent on Zotarolimus coated balloon), and DES (ZoMaxx stent onuncoated balloon), as described in the Comparative Studies. An arbitraryscoring system was used in which 0=still oversized, 1=about referencediameter, 2=slightly less than reference diameter, 3=significantly lessthan reference diameter, 4=very narrow but not included, 5=occluded.

FIG. 8 depicts a graph showing a summary of the results of late lumenloss [mm] assessed by QCA of P (TriMaxx Stent on uncoated balloon), DEB(TriMaxx Stent on Zotarolimus coated balloon), and DES (ZoMaxx stent onuncoated balloon), as described in the Comparative Studies.

FIG. 9 depicts a graph showing a summary of the results of neointimalarea [mm] assessed by histomorphometry of P (TriMaxx Stent on uncoatedballoon), DEB (TriMaxx Stent on Zotarolimus coated balloon), and DES(ZoMaxx stent on uncoated balloon), as described in the ComparativeStudies.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to the present preferredembodiments of the method and system for loading a first beneficialagent onto a prosthesis, and a second beneficial agent onto a balloon.Wherever possible, the same reference characters will be used throughoutthe drawings to refer to the same or like parts.

In accordance with the present invention, a system is provided fordelivery of beneficial agents within a lumen. Particularly, the presentinvention provides a system including a prosthesis having a firstbeneficial agent and a balloon having second beneficial agent where thebeneficial agents are delivered for treatment and prevention of vascularor other intraluminal diseases.

As used herein “interventional device” refers broadly to any devicesuitable for intraluminal delivery or implantation. For purposes ofillustration and not limitation, examples of such interventional devicesinclude stents, grafts, stent-grafts, and the like. As is known in theart, such devices may comprise one or more prostheses, each having afirst cross-sectional dimension or profile for the purpose of deliveryand a second cross-sectional dimension or profile after deployment. Eachprosthesis may be deployed by known mechanical techniques such asballoon expansion deployment techniques, or by electrical or thermalactuation, or self-expansion deployment techniques, as well known in theart. Examples of such for purpose of illustration include U.S. Pat. No.4,733,665 to Palmaz; U.S. Pat. No. 6,106,548 to Roubin et al.; U.S. Pat.No. 4,580,568 to Gianturco; U.S. Pat. No. 5,755,771 to Penn et al.; andU.S. Pat. No. 6,033,434 to Borghi, all of which are incorporated hereinby reference.

For purposes of explanation and illustration, and not limitation, anexemplary embodiment of the interventional device in accordance with theinvention is shown schematically in FIG. 2. In accordance with oneaspect of the invention, as shown schematically in FIG. 2, theinterventional device generally includes a prosthesis loaded withbeneficial agent to provide a local delivery of a first beneficial agentacross a treatment zone and a balloon with a second beneficial agentdelivered a cross a second overlapping treatment zone. Particularly, asembodied herein the prosthesis may be a stent, a graft or a stent-graft,as previously noted, for intravascular or coronary delivery andimplantation. However, the prosthesis may be any type of implantablemember capable of being loaded with beneficial agent. The balloon may beany type of catheter based expandable entity that can act to expand theprosthesis, the local tissue, or push the second beneficial agentagainst the lumen wall.

The prosthesis can be in an expanded or unexpanded state during theloading of beneficial agent. The underlying structure of the prosthesiscan be virtually any structural design and the prosthesis can becomposed any suitable material such as, but not limited to, stainlesssteel, “MP35N,” “MP20N,” elastinite (Nitinol), tantalum, nickel-titaniumalloy, platinum-iridium alloy, gold, magnesium, polymer, ceramic,tissue, or combinations thereof. “MP35N” and “MP20N” are understood tobe trade names for alloys of cobalt, nickel, chromium and molybdenumavailable from Standard Press Steel Co., Jenkintown, Pa. “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium and 10%molybdenum. The prosthesis can be made from bioabsorbable or biostablepolymers. In some embodiments, the surface of the prosthesis can includeone or more reservoirs or cavities formed therein, as described furtherbelow.

The prosthesis can be fabricated utilizing any number of methods knownin the art. For example, the prosthesis can be fabricated from a hollowor formed tube that is machined using lasers, electric dischargemilling, chemical etching or other known techniques. Alternatively, theprosthesis can be fabricated from a sheet that is rolled into a tubularmember, or formed of a wire or filament construction as known in theart.

The balloon can be in an expanded or unexpanded state during the loadingof beneficial agent. Additionally, the balloon can be in a rolled orunrolled state during the loading of beneficial agent. The underlyingstructure of the balloon can be virtually any structural design and theballoon can be composed of any suitable material such as, but notlimited to, polyester, pTFE (Teflon), nylon, Dacron, or combinationsthereof “Teflon” and “Dacron” are understood to be trade names forpolymers available from DuPont Co., Wilmington, Del. In someembodiments, the surface of the balloon can include one or morereservoirs or cavities formed therein or ports for solution delivery.

The balloon can be fabricated utilizing any number of methods known inthe art. For example, the balloon can be fabricated from a hollow orformed tube that is cover with thin membranes of polymer that issolution or physically (by laser or ultrasonically) welded to the tube.The inner volume of the balloon is then in direct contact with the tubesuch that air or aqueous solutions can be injected into the space underpressure to expand the balloon into any predefined shape that is of use.The surface of the balloon can be rolled to reduce the outer diameter ofthe final catheter balloon assemble.

The balloons can be loaded with a beneficial agent from a dilutesolution of the agent made in an appropriate solvent (for exampleEthanol) (if desired this solution could also contain multiplebeneficial agents) and allowed to dry before the stent is crimped ontoit.

Alternatively, the coating could not be allowed to dry or cure past a“tacky” state before the stent is crimped onto it. This would enable theadhesion of the beneficial agent coating on the balloon to the inside ofthe prosthesis. This process increases the retention of the prosthesisonto the balloon (acting as a prosthesis retention enhancer) thusreducing the chance that the stent will move on the angioplasty balloonduring the torturous trip to the coronary arteries. To prevent the filmon the balloon from drying to quickly (i.e. becoming hard before thestent was placed over the balloon) the solution can contain a secondliquid that has a higher boiling point (preferable water) and thus aslower drying time than the main solvent. Additionally, the use of a twosolvent system (i.e. Ethanol-water) would allow the solvent to beadjusted such that the balloons beneficial agent (for exampledexamethasone) is soluble enough to be laid down but the beneficialagent (for example ABT-578, rapamycin, and rapamycin analogies) on theprosthesis is not soluble enough to leach out of the prosthesis into theballoon coating or out of the balloon coating into the prosthesiscoating during the drying time.

Additionally, polymer barriers, timing layers, top or capcoats,especially on the luminal side of the prosthesis, or the use of baremetal interfaces can be used to prevent drug transfer from the balloonsurface into the delivery polymer of the prosthesis. Alternately, someof the beneficial agent from the balloon could be allowed to transfer tothe stent creating a gradient of the two beneficial agents released fromthe stent into the tissue. The binder can be composed of complex sugars(mannitol), starches (e.g., cellulose), collagens. In general the binderwould be noncrystalline, have low water solubility, have good filmforming characteristics, good solubility with solvents that may be usedto dissolve the drug, biocompatible, inert (nonreactive with respect tothe drug and also body tissues, fluids, etc), polymer, (e.g., hydrogel),can be hydrophobic if not hydrogel, especially if it is not permanentlyattached to balloon (if permanently attached, then can use hydrogel, canbe used to absorb drug and then when balloon inflated, will squeeze outthe drug into ablumenal tissue), low blood solubility if not permanentlyattached to balloon

The prosthesis, balloon combination can be fabricated utilizing anynumber of methods known in the art. For example, the prosthesis can beslipped over the end of the balloon and aligned at the center of theballoon. The prosthesis can pre reduced in diameter such that as it isslipped over the end of the balloon there is a tight fit between theprosthesis and the balloon surface. Additionally, the prosthesis can becrimped onto the balloon to ensure that the prosthesis does not moveduring delivery of the prosthesis. The envisioned steps for this processwould be: Dip or spray coat the balloon with the balloons beneficialagent, place the previously beneficial agent coated prosthesis onto adry or tacky balloon and place Balloon/Stent into crimper and crimping.

As noted above, the prosthesis and the balloon are at least partiallyloaded with beneficial agent (10 a, 10 b, 10 c). “Beneficial agent” asused herein, refers to any compound, mixture of compounds, orcomposition of matter consisting of a compound, which produces abeneficial or useful result. The beneficial agent can be a polymer, amarker, such as a radiopaque dye or particles, or can be a drug,including pharmaceutical and beneficial agents, or an agent includinginorganic or organic drugs without limitation. The agent or drug can bein various forms such as uncharged molecules, components of molecularcomplexes, pharmacologically-acceptable salts such as hydrochloride,hydrobromide, sulfate, laurate, palmitate, phosphate, nitrate, borate,acetate, maleate, tartrate, oleate, and salicylate.

An agent or drug that is water insoluble can be used in a form that is awater-soluble derivative thereof to effectively serve as a solute, andon its release from the device, is converted by enzymes, hydrolyzed bybody pH, or metabolic processes to a biologically active form.Additionally, the agents or drug formulations can have various knownforms such as solutions, dispersions, pastes, particles, granules,emulsions, suspensions and powders. The drug or agent may or may not bemixed with polymer or a solvent as desired.

For purposes of illustration and not limitation, the drug or agent caninclude antithrombotics, anticoagulants, antiplatelet agents,thrombolytics, lipid-lowering agents, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, inhibitors ofsmooth muscle cell proliferation, antibiotics, growth factor inhibitors,cell adhesion promoters, or cell adhesion inhibitors. Other drugs oragents include but are not limited to antineoplastics, antimitotics,antifibrins, antioxidants, agents that promote endothelial cellrecovery, antiallergic substances, radiopaque agents, viral vectors,antisense compounds, oligionucleotides, cell permeation enhancers,angiogenesis agents, and combinations thereof.

Examples of such antithrombotics, anticoagulants, antiplatelet agents,and thrombolytics include unfractionated heparin, low molecular weightheparins, such as dalteparin, enoxaparin, nadroparin, reviparin,ardoparin and certaparin, heparinoids, hirudin, argatroban, forskolin,vapriprost, prostacyclin and prostacylin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa (platelet membrane receptor antagonist antibody),recombinant hirudin, and thrombin inhibitors such as Angiomax™, fromBiogen, Inc., Cambridge, Mass.; and thrombolytic agents, such asurokinase, e.g., Abbokinase™ from Abbott Laboratories Inc., NorthChicago, Ill., recombinant urokinase and pro-urokinase from AbbottLaboratories Inc., tissue plasminogen activator (Alteplase™ fromGenentech, South San Francisco, Calif. and tenecteplase (TNK-tPA).

Examples of such cytostatic or antiproliferative agents includerapamycin and its analogs such as ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3Hpyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone,everolimus, tacrolimus and pimecrolimus, angiopeptin, angiotensinconverting enzyme inhibitors such as captopril, e.g, Capoten® andCapozide® from Bristol-Myers Squibb Co., Stamford, Conn., cilazapril orlisinopril, e.g., Prinivil® and Prinzide® from Merck & Co., Inc.,Whitehouse Station, N.J.; calcium channel blockers such as nifedipine,amlodipine, cilnidipine, lercanidipine, benidipine, trifluperazine,diltiazem and verapamil, fibroblast growth factor antagonists, fish oil(omega 3-fatty acid), histamine antagonists, lovastatin, e.g. Mevacor®from Merck & Co., Inc., Whitehouse Station, N.J. In addition,topoisomerase inhibitors such as etoposide and topotecan, as well asantiestrogens such as tamoxifen may be used.

Examples of such anti-inflammatories include colchicine andglucocorticoids such as betamethasone, cortisone, dexamethasone,budesonide, prednisolone, methylprednisolone and hydrocortisone.Non-steroidal anti-inflammatory agents include flurbiprofen, ibuprofen,ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetominophen,indomethacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamicacid, piroxicam and phenylbutazone.

Examples of such antineoplastics include alkylating agents such asaltretamine, bendamucine, carboplatin, carmustine, cisplatin,cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine,prednimustine, and treosulfin, antimitotics such as vincristine,vinblastine, paclitaxel, e.g., TAXOL® by Bristol-Myers Squibb Co.,Stamford, Conn., docetaxel, e.g., Taxotere® from Aventis S.A.,Frankfort, Germany, antimetabolites such as methotrexate,mercaptopurine, pentostatin, trimetrexate, gemcitabine, azathioprine,and fluorouracil, and antibiotics such as doxorubicin hydrochloride,e.g., Adriamycin® from Pharmacia & Upjohn, Peapack, N.J., and mitomycin,e.g., Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn., agentsthat promote endothelial cell recovery such as Estradiol

Additional drugs which may be utilized in this application includeinhibitors of tyrosine kinase such as RPR-101511A, PPAR-alpha agonistssuch as Tricor™ (fenofibrate) from Abbott Laboratories Inc., NorthChicago, Ill., PPAR-gamma agonists selected from a group consisting ofrosiglitazaone (Glaxo Smith Kline) and Pioglitazone (Takeda), HMG CoAreductase inhibitors selected from a group consisting of lovastatin,atorvastatin, simvastatin, pravastatin, cerivastatin and fluvastatin,endothelin receptor antagonists such as ABT-627 having general formulaC₂₉H₃₈N₂O₆.ClH, and the following structural formula

from Abbott Laboratories Inc., North Chicago, Ill.; matrixmetalloproteinase inhibitors such as ABT-518 having general formulaC₂₁H₂₂F₃NO₈S and having the following structural formula

from Abbott Laboratories Inc., North Chicago, Ill., antiallergic agentssuch as permirolast potassium nitroprusside, phosphodiesteraseinhibitors, prostaglandin inhibitors, suramin, serotonin blockers,steroids, thioprotease inhibitors, triazolopyrimidine, and nitric oxide.

While the foregoing beneficial agents are known for their preventive andtreatment properties, the substances or agents are provided by way ofexample and are not meant to be limiting. Further, other beneficialagents that are currently available or may be developed are equallyapplicable for use with the present invention.

If desired or necessary, the beneficial agent can include a binder tocarry, load, or allow sustained release of an agent, such as but notlimited to a suitable polymer or similar carrier. The term “polymer” isintended to include a product of a polymerization reaction inclusive ofhomopolymers, copolymers, terpolymers, etc., whether natural orsynthetic, including random, alternating, block, graft, branched,cross-linked, blends, compositions of blends and variations thereof. Thepolymer may be in true solution, saturated, or suspended as particles orsupersaturated in the beneficial agent. The polymer can bebiocompatible, or biodegradable.

For purpose of illustration and not limitation, the polymeric materialinclude phosphorylcholine linked macromolecules, such as a macromoleculecontaining pendant phosphorylcholine groups such aspoly(MPC_(w):LMA_(x):HPMA_(y):TSMA_(z)), where MPC is2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate, polycaprolactone, poly-D,L-lactic acid, poly-L-lacticacid, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen,cellulose, starch, collagen, Parylene®, Parylast®, polyurethaneincluding polycarbonate urethanes, polyethylene, polyethyleneterephthalate, ethylene vinyl acetate, ethylene vinyl alcohol, siliconeincluding polysiloxanes and substituted polysiloxanes, polyethyleneoxide, polybutylene terephthalate-co-PEG, PCL-co-PEG, PLA-co-PEG,polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinationsthereof. Non-limiting examples of other suitable polymers includethermoplastic elastomers in general, polyolefin elastomers, EPDM rubbersand polyamide elastomers, and biostable plastic material such as acrylicpolymers, and its derivatives, nylon, polyesters and epoxies.Preferably, the polymer contains pendant phosphoryl groups as disclosedin U.S. Pat. Nos. 5,705,583 and 6,090,901 to Bowers et al. and U.S. Pat.No. 6,083,257 to Taylor et al., which are all incorporated herein byreference.

The beneficial agent can include a solvent. The solvent can be anysingle solvent or a combination of solvents. For purpose of illustrationand not limitation, examples of suitable solvents include water,aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones,dimethyl sulfoxide, tetrahydrofuran, dihydrofuran, dimethylacetamide,acetates, and combinations thereof. Preferably, the solvent is ethanol.More preferably, the solvent is isobutanol. Additionally, in anotheraspect of the invention, multiple beneficial agents are dissolved ordispersed in the same solvent. For purpose of illustration and not forlimitation, dexamethasone, estradiol, and paclitaxel are dissolved inisobutanol. Alternatively, dexamethasone, estradiol, and paclitaxel aredissolved in ethanol. In yet another example, dexamethasone, estradiol,and ABT-578, i.e., the rapamycin analog,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23-S,26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone,are dissolved together in one solvent. Preferably, the solvent isethanol. More preferably, the solvent is isobutanol.

Additionally, the beneficial agent includes any of the aforementioneddrugs, agents, polymers, and solvents either alone or in combination.

A number of methods can be used to load the beneficial agent onto thesurface of the prosthesis or balloon to provide for a controlled localareal density of beneficial agent. For example, the prosthesis orballoon can be constructed to include pores or reservoirs which areimpregnated or filled with beneficial agent or multiple beneficialagents. The pores can be sized or spaced apart to correspond to or limitthe amount of beneficial agent contained therein in accordance with thedesired local areal density pattern along the length of theinterventional device, wherein larger pores or more dense spacing wouldbe provided in such portions intended to have a greater local arealdensity. Alternatively, uniform pores sizes can be provided but theamount of beneficial agent loaded therein is limited accordingly.Additionally, if desired, a membrane of biocompatible material can thenbe applied over the pores or reservoirs for sustained or controlledrelease of the beneficial agent from the pores or reservoirs.

According to some of the embodiments, the beneficial agent can be loadeddirectly onto the prosthesis or balloon or alternatively, the beneficialagent is loaded onto a base material layer that is applied to a surfaceof the prosthesis or balloon. For example and not limitation, a basecoating, such as a binder or suitable polymer, is applied to a selectedsurface of the prosthesis or balloon such that a desired pattern isformed on the prosthesis or balloon surface. Beneficial agent is thenapplied directly to the pattern of the base material.

In one aspect of the invention, the desired pattern corresponds to thedesired controlled local areal density. For example, a greater amount ofbase material layer is applied to portions of the prosthesis or balloonintended to have a greater local areal density of beneficial agent, anda lesser amount of base material is applied to portions of theprosthesis or balloon intended to have a lower local areal density ofbeneficial agent.

Alternatively, a suitable base coating capable of retaining beneficialagent therein can be applied uniformly over the surface of theprosthesis or balloon, and then selected portions of the base coatingcan be loaded with the beneficial agent in accordance with theinvention. A greater amount of beneficial agent would be loaded over aunit surface area of the base coating intended to have a greater localareal density and a lower amount of beneficial agent would be loadedover a unit surface area intended to have a lower local areal density.

In yet another embodiment of the present invention, the beneficial agentcan be applied directly to the surface of the prosthesis or balloon.Generally a binder or similar component can be required to ensuresufficient adhesion. For example, this coating technique can includeadmixing the beneficial agent with a suitable binder or polymer to forma coating mixture, which is then coated onto the surface of theprosthesis or balloon. The coating mixture is prepared in higher orlower concentrations of beneficial agent as desired, and then applied toselected portions of the prosthesis or balloon appropriately. In generalthe binder used with the beneficial agent for the prosthesis may bedifference then the binder used for the beneficial agent for theballoon.

In any of the embodiments disclosed herein, a porous or biodegradablemembrane or layer made of biocompatible material can be coated over thebeneficial agent for sustained release thereof, if desired.

Conventional coating techniques can be utilized to coat the beneficialagent onto the surface of the prosthesis or balloon such as spraying,dipping or sputtering and still provide the desired effect if performedappropriately. With such techniques, it may be desirable or necessary touse known masking or extraction techniques to control the location andamount in which beneficial agent is loaded. Although not required, priorto coating the prosthesis or balloon with beneficial agent, opticalmachine vision inspection of the prosthesis or balloon may be utilizedto ensure that no mechanical defects exist. Defective prostheses orballoons may be rejected before wasting beneficial agent, some of whichmay be very costly.

In accordance with one aspect of the invention, a method of loadingbeneficial agent onto a prosthesis for delivery within a lumen isdisclosed. The method comprises the steps of providing a prosthesis,beneficial agent to be delivered from the prosthesis, and afluid-dispenser having a dispensing element capable of dispensing thebeneficial agent in discrete droplets, wherein each droplet has acontrolled trajectory. The method further includes creating relativemovement between the dispensing element and the prosthesis to define adispensing path and selectively dispensing the beneficial agent in araster format to a predetermined portion of the prosthesis along thedispensing path. In particular, the beneficial agent is selectivelydispensed from the dispensing element to a predetermined portion of theprosthesis in a raster format along a dispensing path. As used herein“raster format” refers to a continuous or non-continuous dispensingpattern of droplets of beneficial agent.

According to another aspect of the invention, the method of loadingbeneficial agent onto the prosthesis includes providing a prosthesisincluding a tubular member having a central axis defined along a lengthof the tubular member. This method further includes dispensingbeneficial agent

In accordance with another aspect of the invention, additionalbeneficial agents or multiple beneficial agents can be loaded onto theprosthesis as described above. Therefore, further in accordance with theinvention, an interventional device comprising a prosthesis loaded witha beneficial agent and additional beneficial agents is provided.

Particularly, the method described in detail above for one beneficialagent can be modified to allow for loading multiple beneficial agentsonto a prosthesis and/or a balloon, which might ordinarily lead toundesirable results when using conventional loading techniques. Forexample and not limitation, the first beneficial agent and the secondbeneficial agent may have different physical and/or chemicalcharacteristics preventing the beneficial agents from being capable ofdissolving in the same solvent, or at the same pH or temperature. Inparticular, the first beneficial agent can be dissolved in a solventthat is immiscible with the solvent in which the second beneficial agentis dissolved. Alternatively, the first beneficial agent and the secondbeneficial agent may be incompatible with each other. In particular, thefirst beneficial agent and the second beneficial agent can beundesirably chemically reactive or may have undesirably differentrelease rates (or contrarily, undesirably similar release rates).Additionally, the first and second beneficial agents can simply bedetrimental to each other, e.g., one of the beneficial agents maydegrade the efficacy of the other beneficial agent. Thus, althoughloading the particular multiple beneficial agents onto the same surfaceof a prosthesis or balloon can be desired it often may be problematicdue to some incompatibility when using a conventional loading technique.In accordance with the present invention, a method of loading suchbeneficial agents and an interventional device that combine a prosthesisand a balloon for the delivery of such beneficial agents is provided.

As noted above, the beneficial agent can include a drug and polymermixture. In accordance with the method of the invention, the first andsecond beneficial agents can correspond to drug-polymer mixtures havingdifferent concentrations of polymer to effect different release rates ofthe particular drug in each beneficial agent. For example, thedrug-polymer mixture having a higher concentration of polymer would havea slower release of the drug within the lumen than a drug-polymermixture having a lower concentration. Alternatively, rather thanproviding drug-polymer mixtures having different polymer concentrationsto provide different release rates, it is also possible to dispensebeneficial agents using different polymers or other binders, wherein thespecific polymer or binder has different diffusivity or affinity toassure delivery of the beneficial agents at different rates. Thus, inaccordance with the invention, multiple beneficial agents can bereleased at rates appropriate for their activities, such that theprosthesis-balloon combination of the invention has multiple beneficialagents which elute off the prosthesis-balloon combination at desiredrates.

For example, a cationic phosphorylcholine-linked polymer which has ahigher affinity for anionic beneficial agents can be blended anddispersed as a first beneficial agent and lipophilicphosphorylcholine-linked polymer can be blended with lipophilic drugs asthe second beneficial agent to effect different release ratesrespectively.

In yet another embodiment of the invention, one of the first and secondbeneficial agents loaded onto the prosthesis-balloon combination may bemore hydrophobic than the other. Thus, in accordance with the inventionis provided a prosthesis-balloon combination including first and secondbeneficial agents wherein one of the beneficial agents is morehydrophobic than the other. In this manner, the less hydrophobicbeneficial agent is separated from the more hydrophobic beneficialagent, thereby not modifying the release rate of the more hydrophobicbeneficial agent. For example and not limitation, the less hydrophobicbeneficial agent may be ABT 620{1-Methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide}, which isdisclosed in U.S. Pat. No. 6,521,658, the disclosure of which isincorporated herein by reference; ABT 627, which is disclosed in U.S.Pat. No. 5,767,144, the disclosure of which is incorporated herein byreference; ABT 518{[S—(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoro-methoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide},which is disclosed in U.S. Pat. No. 6,235,786, the disclosure of whichis incorporated herein by reference; dexamethasone, and the like and themore hydrophobic beneficial agent may be Fenofibrate, Tricor™ or therapamycin analog, ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone,which is disclosed in U.S. Pat. No. 6,015,815, U.S. Pat. No. 6,329,386,WO 02/123505, and WO 03/129215, disclosures of which are incorporatedherein by reference thereto.

Further in accordance with the invention, using the method and systemsdescribed above, a first beneficial agent loaded onto the prosthesis canhave a first local areal density and a second beneficial agent loadedonto the balloon can have a second local areal density. As used herein,“areal density” refers to the amount of beneficial agent per unitsurface area of a selected portion of the prosthesis or balloon. “Localareal density” refers to the dosage of beneficial agent per localsurface area of the prosthesis or balloon. The local areal density ofthe first beneficial agent and the local areal density of the secondbeneficial agent can be uniform across each respective portion to definestepped changes in local area density as depicted in FIG. 5B or can bevaried across a selected portion of the prosthesis or balloon to definegradients of local area density, as depicted in FIG. 5C. Accordingly, aninterventional device is provided having a prosthesis or balloon that isat least partially loaded with beneficial agent having a local arealdensity that is varied along a selected portion of the body of theprosthesis or balloon.

In another embodiment of the invention, the local areal density isvaried as a continuous gradient along a selected portion of theprosthesis or balloon as shown in FIG. 5C. Accordingly, in one aspect ofthe invention the local areal density of beneficial agent is varied suchas to provide a prosthesis or balloon having a local areal density ofbeneficial agent at the ends of the prosthesis or balloon that isdifferent than the local areal density of beneficial agent at anintermediate section of the prosthesis or balloon. For purpose ofillustration and not limitation, the local areal density of beneficialagent at the intermediate section of the prosthesis can be greater thanthat at the proximal and distal ends of the prosthesis as shown in FIG.5C. Alternatively, the proximal and distal ends of the prosthesis canhave a greater local areal density of beneficial agent than that on theintermediate section of the prosthesis. In a preferred embodiment of theinvention, the varied local areal density of beneficial agentcorresponds to the location of a lesion when the prosthesis is deployedwithin a lumen. For example, the prosthesis or balloon can be loaded tohave a greater local areal density of beneficial agent along apreselected portion of the prosthesis or balloon that corresponds to thelocation of the lesion when the prosthesis is deployed in a lumen. Thus,targeted therapy may be achieved with the interventional device of thepresent invention.

As noted above, the beneficial agent is at least partially loaded onto asurface of the prosthesis. Further in accordance with the invention theprosthesis includes a first surface and a second surface that are atleast partially loaded with beneficial agent. In one embodiment of theinvention, the first surface and the second surface each correspond toone of the inner surface and the outer surface of the prosthesis. Thus,according to this particular embodiment, beneficial agent, as definedabove, is loaded onto the inner or luminal surface of a prosthesis aswell as the outer surface of the prosthesis. In this aspect of theinvention, the interventional device can be designed to providecombination therapy of beneficial agents to targeted locations. Forexample and not limitation, the particular beneficial agent loaded onthe balloon can be intended for systemic or down stream release, whereasthe particular beneficial agent loaded onto the surface of theprosthesis is intended for release into the wall of the vessel. Inaccordance with one aspect of the invention, the beneficial agentsloaded onto the balloon include, without limitation, antiplateletagents, aspirin, cell adhesion promoters, agents that promoteendothelial recovery, agents that promote migration, estradiol,anti-inflammatories, anti-proliferatives, smooth muscle inhibitors, celladhesion promoters, and the rapamycin analog ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.The beneficial agents loaded onto the prosthesis include withoutlimitation, antiplatelet agents, aspirin, cell adhesion promoters,agents that promote endothelial recovery, agents that promote migration,estradiol, anti-inflammatories, anti-proliferatives, smooth muscleinhibitors, cell adhesion promoters, angiotensin II receptor antagonistssuch as losartan, eposartan, valsartan and candesartan, antihypertensiveagents such as carvedilol, and the rapamycin analog ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.

As noted above, the beneficial agent is loaded onto the prosthesis toprovide a controlled local areal density across a length of theinterventional device. That is, it may be desirable to provide a greaterconcentration of beneficial agent at one portion of a prosthesis and alower concentration, or perhaps no beneficial agent, at another portionof the prosthesis. For example, in one preferred embodiment, a greaterlocal areal density can be provided at a first portion, e.g.,intermediate portion 10 b, of a prosthesis or balloon 10, as shown inFIG. 5A, while providing a lower local areal density of beneficial agentto a second portion, e.g., one or both end portions (10 a, 10 c), of theprosthesis or balloon 10. In accordance with the present invention, eachof the first and second portions of the prosthesis or balloon may bedefined by any of a variety of patterns or selected portions of theprosthesis or balloon. For example, the first portion of the prosthesiscan be defined by longitudinal connectors whereas the second portion ofthe prosthesis is defined by annular rings, or vice versa.

Alternatively, the beneficial agent distribution profile for theinterventional device may be controlled to include any of a variety ofdesired patterns. For example, the prosthesis or balloon can have adecreased local areal density of beneficial agent on the distal andproximal ends, as noted above. This profile is highly desirable inpreventing adverse dosing of beneficial agent if multiple prostheses areplaced in combination with each other (for example overlappingprostheses or kissing prostheses at bifurcations) but still provides fordecreased dosage of the extreme ends of the interventional device as awhole. Alternatively, as embodied herein, the beneficial agentdistribution profile can provide a controlled local areal density thatis uniform along the length of a first prosthesis and a secondprosthesis in combination, or multiple prostheses in combination.Alternatively, in accordance with the invention, the beneficial agentdistribution profile provides a controlled local areal density that isvaried along the length of the first prosthesis and the secondprosthesis in combination, or multiple prostheses in combination.

Another feature of the present invention includes applying a layer ofbase material on a selected portion of the prosthesis or balloondescribed above. The beneficial agent is loaded onto the base materiallayer according to the methods described above. The base material layerpreferably defines a pattern for loading the beneficial agent onto theprosthesis or balloon.

The present invention also encompasses, for any of the embodimentsdisclosed, the application of a rate-controlling topcoat over thebeneficial agent loaded prosthesis, balloon, or prosthesis-ballooncombination for further controlling or sustaining the release ofbeneficial agent. The rate-controlling topcoat may be added by applyinga coating layer posited over the beneficial agent loaded prosthesis,balloon, or prosthesis-balloon combination. The thickness of the layeris selected to provide such control. Preferably, the overcoat is appliedby spray coating or fluid jet technology. Advantageously, fluid jettingan overcoat such as a polymer overcoat allows thinner and more uniformlayers. However other conventional methods can be used such as otherfluid-dispensers, vapor deposition, plasma deposition, spraying, ordipping, or any other coating technique known in the art.

The present invention also encompasses, for any of the embodimentsdisclosed, the application of polymer barriers, timing layers, top orcapcoats, especially on the luminal side of the prosthesis, or the useof bare metal interfaces to be used to prevent drug transfer from theballoon surface into the delivery polymer of the prosthesis.Alternately, some of the beneficial agent from the balloon could beallowed to transfer to the stent creating a gradient of the twobeneficial agents released from the stent into the tissue.

The present invention also provides a method for manufacturing aninterventional device for delivery of beneficial agents. This methodcomprises the steps of providing a prosthesis to be deployed within alumen; providing a balloon configured to be deployed in an overlappingrelationship with the prosthesis, the prosthesis and the balloon incombination defining at least an overlapping segment; and loading theprosthesis with a first beneficial agent and the balloon with a secondbeneficial agent to provide a controlled local areal density along alength of the prosthesis and the balloon in combination. The methoddescribed in detail above is preferred for such loading step.

The present invention also provides a method of delivering beneficialagents. In accordance with this method, as described in detail inconjunction with the description of the interventional device of thepresent invention above, the method comprising the steps of providing aprosthesis having a tubular body when deployed in a lumen; providing aballoon capable of expanding in the lumen; loading the prosthesis with afirst beneficial agent and the balloon with a second beneficial agent;deploying the prosthesis into a lumen with the beneficial agent coatedballoon deploying the beneficial agent coated prosthesis into the lumento define in combination at least one overlapping segment; wherein thebeneficial agents are loaded onto the prosthesis and the balloon toprovide a controlled local areal density of beneficial agent across alength of the prosthesis when deployed. The method described in detailabove is preferred for such loading step.

For purposes of explanation and illustration, and not limitation, anexemplary embodiment of the interventional device in accordance with theinvention is shown schematically in FIGS. 2 and 3. In accordance withone aspect of the invention, as shown schematically in FIGS. 2 and 3,the interventional device generally includes a prosthesis loaded withbeneficial agent (preferably ABT-578, rapamycin, or rapamycin analogies,alone or in combination with an additional drug such as dexamethasone orestradiol) to provide a local delivery of a first beneficial agentacross a treatment zone and a balloon with a second beneficial agent(preferably paclitaxel, taxanes, or other taxane derivatives, alone orin combination with an additional drug) delivered a cross a secondoverlapping treatment zone. Alternatively, the a prosthesis could beloaded with beneficial agent (preferably paclitaxel, taxanes, or othertaxane derivatives alone or in combination with an additional drug suchas dexamethasone or estradiol) to provide a local delivery of a firstbeneficial agent across a treatment zone and a balloon with a secondbeneficial agent (preferably ABT-578, rapamycin, or rapamycin analogies,alone or in combination with an additional drug) delivered a cross asecond overlapping treatment zone. Particularly, as embodied herein theprosthesis may be a stent, a graft or a stent-graft, as previouslynoted, for intravascular or coronary delivery and implantation. However,the prosthesis may be any type of implantable member capable of beingloaded with beneficial agent. The balloon may be any type of catheterbased expandable entity that can act to expand the prosthesis, the localtissue, or push the second beneficial agent against the lumen wall.

In an alternative embodiment, as shown schematically in FIGS. 6A and 6B,the balloon catheter does not have a prosthesis thereon. As illustratedin FIGS. 6A and 6B, the balloon surface is coated with a beneficialagent.

The present invention will be further understood by the examples setforth below, which are provided for purpose of illustration and notlimitation.

The following examples demonstrate how various embodiments of thepresent invention may be practiced. By “simultaneous” it is meant that acoated prosthesis (e.g., stent) is mounted on a coated balloon and thestent and balloon are delivered to the desired location at the sametime. By “independent”, it is meant that the coated balloon is deliveredeither before or after the coated stent is delivered. By “combined”, itis meant that beneficial agent(s) are delivered from both the balloonand the prosthesis to the vessel tissue.”

EXAMPLES Example 1 Loading of Stents with Beneficial Agents or MultipleBeneficial Agents

I. Coating the Stents with PC1036

Prior to any experimentation, coated stents are prepared. These are 3.0mm×15 mm 316 L electropolished stainless steel stents. Each stent isspray coated using a filtered 20-mg/mL solution of phosphorylcholinepolymer PC1036 (product of Biocompatibles Ltd., Farnham, Surrey, UK) inethanol. The stents are initially air dried and then cured at 70° C. for16 hours. They are then sent for gamma irradiation at <25 KGy.

II. Loading the Stents with Drugs of Interest

In these experiments, beneficial agents are loaded onto stents andelution profiles examined. In general, the procedure is as follows.Multiple PC-coated stents are loaded with each of several drugs orcombinations thereof from solution. The solutions of the drugs areusually in the range of 2-20 mg/mL of ABT-578 and 10.0 mg/mLdexamethasone in 100% ethanol, with ˜10% PC1036 added to the solution toenhance film formation.

The stents are weighed before loading with the drug solution. To loadapproximately 10 μg/mL of each drug, a solution with equal amounts ofABT-578 and dexamethasone is sprayed onto the stent in a controlledfashion. The stent is allowed to dry before the stents are re-weightedto determine total drug load. The loaded, dry stents are stored in arefrigerator and are protected from light.

III. Extracting Drugs from the Stents

For each drug, 3 stents are used to evaluate the total amount of drugloaded by the above procedure. The stents are immersed in 6 mL of 50%ethanol, 50% water solution and sonicated for 20 minutes. Theconcentration of the drug in the extraction solution is analyzed byHPLC.

Example 2 Loading of Balloons with Beneficial Agents or MultipleBeneficial Agents I. Preparing the Balloon for Drug Loading

Multiple balloons (Jomed 15 mm×3.0 mm) are rolled to minimize the finalcatheter crossing profile. If needed the balloons where washed inethanol.

II. Loading the Balloon with Drugs of Interest

In these experiments, beneficial agents are loaded onto balloons. Ingeneral, the procedure is as follows. Multiple balloons (Jomed 15 mm×3.0mm) are loaded with paclitaxel from a solution. The solutions ofpaclitaxel are usually in the range of 2-20 mg/mL of paclitaxel in 100%ethanol.

The balloons are weighed before loading with the drug solution. To loadapproximately 200 to 600 ug of paclitaxel, the balloons are dipped intoa solution of paclitaxel. The balloon is removed in a controlled fashionto control drying. The stent is allowed to dry before the balloons arere-weighed to determine total drug load. The loaded, dry balloons arestored at room temperature and are protected from light.

III. Extracting Drugs from the Balloon

For each drug, 3 balloons are used to evaluate the total amount of drugloaded by the above procedure. The balloons are expanded and immersed in6 mL of 50% ethanol, 50% water solution and sonicated for 20 minutes.The concentration of the drug in the extraction solution is analyzed byHPLC.

Example 3 Crimping of Beneficial Agent-Coated Stents onto BeneficialAgent-Coated Balloons

Multiple stents loaded with ABT-578 and top coated with PC1036 areplaced over the end of catheter balloons which have been coated withpaclitaxel. The stent is centered over the radiopaque markers of theballoon and crimped onto the balloon using a Machine Solutions drugeluting stent crimper. The stent-balloon final product is thenleak-tested and visually inspected to ensure the quality of the finalproduct. The catheter assembly is then packaged in Tyvek pouches,labeled, and ETO sterilized.

Example 4 Simultaneous Combined Delivery of a First Beneficial Agent onProsthesis and a Second Beneficial Agent on Balloon

This example describes delivery of a stent containing at least onebeneficial agent using a balloon coated with a second beneficialagent(s). In this example, a prosthesis will be coated with at least onebeneficial agent and will be mounted on an angioplasty balloon, whichhas been coated with a second beneficial agent(s). This complete systemwill be inserted into the body via a peripheral vessel, and advanced tothe lesion targeted for treatment. After location at the lesion site,the angioplasty balloon containing the second beneficial agent(s) willbe expanded, simultaneously delivering said beneficial agent(s) as wellas deploying the prosthesis containing the first beneficial agent(s).The simultaneous delivery will use a technique often described as directstenting, in which no pre-dilatation of the vessel at the site of thelesion is involved and the delivery of each beneficial agent beginsduring the same time period. Alternatively, the simultaneous deliverycan be completed after pre-dilatation with an uncoated balloon or with acoated balloon. When deployment of the prosthesis is complete, theballoon will be deflated and removed from the body, leaving theprosthetic device in place to continue delivering the first beneficialagent(s) over time. Beneficial agents on the prosthesis or the ballooncan be the same or different.

Example 5 Independent Combined Delivery of First Beneficial Agent(s) onProsthesis and Second Beneficial Agent(s) on Balloon

A balloon coated with one or more beneficial agents, but containing noprosthesis, will be inserted into the body, and advanced to the lesionsite where it will be dilated to expand the vessel. This technique iscommonly described as pre-dilatation. Delivery of a second beneficialagent(s) to the lesion site will proceed upon expansion of this balloon.The balloon will then be deflated and removed from the body. At thattime, a second intervention, in which a second balloon without abeneficial agent, containing a prosthesis coated with one or morebeneficial agents, will be introduced via the peripheral vessel. Uponexpansion of the second balloon at the pre-dilated lesion site, theprosthesis will be expanded and will begin to deliver one or morebeneficial agents to the lesion. The second balloon will then be removedfrom the body.

Example 6 Independent Combined Delivery of First Beneficial Agent(s) onProsthesis with a Post-Expansion Delivery of a Second BeneficialAgent(s) from a Balloon

This procedure involves the delivery of a prosthesis containing a firstbeneficial agent(s), using a balloon that has no beneficial agent. Inthis case, the balloon catheter, containing a drug-loaded prosthesis, isadvanced to the lesion site, and expanded to deliver the device andinitiate the delivery of the beneficial agent(s). The balloon is thendeflated and removed from the body. At this time, a second balloon,coated with a second beneficial agent(s), is inserted into theperipheral vessel and advanced to the lesion site. A second balloonexpansion is then conducted to further expand the previously placedstent or to deliver a second beneficial agent or agents to the site ofthe lesion. Beneficial agents on the prosthesis or the balloon can bethe same or different.

Example 7 Delivery of a Second Beneficial Agent on Balloon to Treatin-Stent Restenosis

This intervention involves the dilation of a vessel with a balloon thatis coated with a second beneficial agent(s) at a restenosed lesion sitewhere a stent or stents have been previously placed. In this way,restenosis of a vessel in which an intervention has previously failedcan be adequately treated without placement of an additional prosthesisor prosthesis at the same site.

Comparative Studies

This study compared the effects of Zotarolimus coated angioplastyballoons and Zotarolimus coated stents on the reduction of formation ofneointima commonly associated with restenosis. Also evaluated was theinfluence of Zotarolimus delivered to one coronary artery from a balloonor stent to neotintimal hyperplasia in a separate coronary arteryimplanted with a bare metal stent. The results of this study indicatethe delivery of beneficial agent directly from an angioplasty balloon isan attractive alternative to a drug eluting stent.

Study Design/Methods A. Animals

Domestic Sus Scrofa male, castrated adolescent pigs weighing between 25to 30 kg were used in these studies. Pigs were acquired from V. B. Zuchtand Mast GmbH, Dorfstraβe 12, 39307 Klein Demsin, Germany. During a tenday (minimum) quarantine period and for four additional days, pigsselected from the animal population were given a corn-based high-fiberfeed and unfiltered tap water was provided ad libitum. Samples of thewater were analyzed for total dissolved solids, harness, specifiedmicrobiological content and selected environmental contaminants. Noknown contaminants were identified which would be expected to interferewith the study. The animals were held in quarantine for a minimum of tendays to ensure the health of each animal before the initiation of thestudy.

B. Interventional Procedure and Surgical Preparation

The pigs were pre-sedated by intramuscular injection of ketamine andxylazine. A venous access was provided. After sedation, the animals wereintubated and maintained in anesthesia with intravenous 3 to 10 mlPropofol (Recofol® 1% (Curamed Pharma GmbH, Germany)). The pigs wereintubated (Endonorm 6.5 F, Rusch GmbH, Germany) and ventilation wasstarted using a mixture of 30 vol. % of pure oxygen, 70 vol % N₂O and1-2 vol % of Isofluran (Isofluran Curamed®, Curamed Pharma GmbH,Germany). After induction of anesthesia, an incision was made in theneck to expose the carotid artery. An arterial sheath was introduced andadvanced into the artery. For the interventional procedure, the animalsreceived 5,000 IU of heparin, 250 mg aspirin intravenously (Aspisol®,Bayer AG, Germany), and intracoronary nitroglycerin.

In each of forty-two pigs, one TriMaxx® stent (P) mounted on a bareangioplasty balloon was implanted in a randomly selected artery, i.e.,left anterior descending coronary artery (LAD) or left circumflexcoronary artery (CX). The remaining coronary vessel was randomlyassigned to receive either: (a) a second TriMaxx® stent on a bareballoon (P), (b) a TriMaxx® stent on a drug-eluting balloon (DEB), or(c) a ZoMaxx® drug eluting stent on a bare balloon (DES). Thus, one setof fourteen pigs received two TriMaxx® stents mounted on bareangioplasty balloons in LAD and CX (P-P), a second set of fourteen pigsreceived one TriMaxx® stent mounted on a bare angioplasty balloon in onecoronary artery and a TriMaxx® stent on a drug eluting balloon in theother artery (P-DEB), and a third set of fourteen pigs received aTriMaxx® stent mounted on a bare angioplasty balloon in one artery and aZoMaxx® drug eluting stent on a bare angioplasty balloon in the othercoronary arty (P-DES).

The placebo control was a TriMaxx® Coronary Stent coated withphosphorylcholine (PC) mounted on a PTCA catheter. The drug elutingstent was a ZoMaxx® Coronary Stent coated with PC and Zotarolimuspremounted on a PTCA catheter and the drug eluting balloon was anangioplasty balloon coated with Zotarolimus premounted with a TriMaxx®Coronary Stent.

The coating solution was 0.7 ml ethanol+150 ul Ultravist 370+4.15 mlacetone; thereof 3 ml+135 mg Zotarolimus=45 mg Zotarolimus/mlZotarolimus. Ethanol content of the solution: 14%. The balloons werecoated two times to achieve 13 μl (3.0-17 mm) or 15 μl (3.5-17 mm) byeither an automatically adjustable 50 μl or a conventional 25 μlHamilton syringe. Total consumption/coating step=47×13 μl+59×15μl+losses=1.5 ml+losses. The drying time between coatings was >3 hrs.

TABLE I Summary of Coating μg/mm² μg/mm μg balloon balloon Samples nZotarolimus surface length % of dose Unused coated balloons with 5 1 200± 46  6.4 ± 0.2 71 ± 3 100 stents 3.5-17 mm Unused coated balloons with4 1073 ± 56 6.7 ± 0.3 63 ± 3 100 stents 3.0-17 mm Coated balloons afteruse 15  131 ± 60  7.7 ± 3.5 14.1 ± 11.5 Bare balloons with premounted 4not detectable ZoMaxx stents after use Bare balloons with 3 notdetectable bare stents after use

The Zotarolimus content of balloons with stents and balloon after stentimplantation was calculated and summarized at Table II.

TABLE II Zotarolimus Content of Balloons With Stents And Balloons AfterImplantation Sample/ Peak area Peak area Total Conc. ABT ABT-578 % ofAnimal no*** ABT Oxepane area μg/ml μg dose 25 μg/ml 722,842 43,851766,693 25.00 0 18/3.5-17 21 439 952  1 620 115   23 060 067  752 1 12831/3.5-17 22 734 940  1 731 578   24 466 518  798 1 197 38/3.5-17 23 266330  1 718 515   24 984 845  815 1 222 44/3.5-17 22 843 718  1 669 004  24 512 722  799 1 199 54/3.5-17 23 859 656  1 772 667   25 632 323  8361 254 Mean ± SD 1 200 ± 46   71/3.0-17 20 545 884  1 629 657   22 175541  723 1,085 72/3.0-17 10 559 856  1 576 729   12 13 585 396 59488/3.0-17 20 476 530  1 601 586   22 081 116  720 1,080 90/3.0-17 18 874040  1 491 887   20 365 927  664 996 98/3.0-17 21 480 138  1 648 244  23 128 382  754 1,131 Mean ± SD 1073 ± 56* 16**/14 CX 1 206 986  93 2071 300 193 42.5 63.8 5.3 19/5 CX 1 186 017 101 098 1 287 115 42.0 63.05.2 22/43 CX 2 474 350 175 955 2 650 305 86.7 130 10.8 25/20 LAD 2 266034 159 360 2 425 394 79.3 119 9.9 26/7 CX 1 129 959  71 187 1 201 14639.2 58.8 4.9 28/2 LAD 1 817 150 143 416 1 960 566 63.9 95.9 8.0 36/32LAD 4 119 968 300 699 4 430 667 145 217 18.1 37/34-36 LAD 2 600 973 186731 2 787 704 91.2 137 11.4 43/3 CX 5 247 028 394 311 5 641 339 184 27623.0 48**/21 CX 2 621 613 195 138 2 816 751 92.1 138 11.5 49/17 LAD 3526 794 261 929 3 788 723 124 186 15.5 51/19 LAD 2 996 942 221 358 3 218300 105 158 13.2 53/10 LAD 2 112 427 145 245 2 257 672 73.8 111 9.256/24 CX 2 232 040 161 731 2 393 771 78.3 117 9.8 92**/13 CX 1 828 869135 997 1 964 866 64.3 96.4 9.0 131 ± 60 14.1 ± 11.5 DES/17 no peakDES/23 no peak DES/27 no peak DES/28 no peak No drug/3LAD no peak Nodrug/19 CX no peak No drug/2CX no peak **more blood than on otherballoons

The Zotarolimus measurements were made according to the followingmethod, the gradient clean up was not performed. Zorbax Eclipse XDB-C8columns sized 4.6×75 mm by 3.5 micrometers, the column temperature of 45degrees centigrade at a flow rate of 1 ml/min, the flow media 51%ammonia acetate buffer ph 4.9; 49% acetone nitrile, injection volume 20micro liters, UV detection 278 nm.

Each stent delivery system was prepared by flushing the guidewire lumenwith heparinized saline solution. Air was aspirated from the balloonlumen using negative pressure, filling lumen with a 50/50 mixture of0.9% normal saline and contrast solution. Stents were then introducedinto the coronary arteries by advancing the stented balloon catheterthrough the guide catheter and over the guidewire to the deployment sitewithin the LAD or CX. The balloon was then inflated at a steady rate toa pressure sufficient to target a stent: artery ratio of 1.2.Confirmation of this stent-artery ratio was made when the angiographicimages were quantitatively assessed. After the target balloon to arteryratio was achieved for 60 seconds, vacuum was applied to the inflationdevice in order to deflate the balloon. The delivery system was removed.

Contrast injections were used to determine device patency and additionalacute system was noted. This process was repeated until all devices weredeployed. All catheters were then removed from the animal and thecarotid artery was ligated. At this time, blood pressure monitoring wasterminated. The incision was closed in layers with suture materials. Theskin was closed with closure materials. The pigs were returned to theircages and allowed to recover from anesthesia. To prevent infection, pigswere given Urocyclin 10% at appropriate dosage levels at least 1 dayprior to implantation and on the day of implantation. Additional doseswere administered as necessary.

After 28 days, the pigs were sacrificed using pentobarbital in deepanesthesia. Hearts were rapidly excised, the coronary system flushedwith 0.9% saline and the arteries fixed by perfusion with 4% bufferedformalin under physiological pressure and overnight immersion. Thetarget segments were then dissected and samples for histology obtained.

C. Data Collection

1. Semi-Quantitative and Quantitative Coronary Analysis (QCA)

Coronary imaging was done using a Philips PolyArc fluoroscope connectedto a digitizer using an Apple Macintosch Power PC. A semi-quantitativeevaluation of coronary angiography was performed with the followinggrading: 0=no signs of neointimal hyperplasia (identical with resultimmediately after stent implantation); 1=slight signs of neointimalhyperplasia; 2=moderate signs of neointimal hyperplasia (minimal lumendiameter in-stent identical with vessel reference diameter); 3=clearsigns of neointimal hyperplasia (minimal lumen diameter in-stentidentical with vessel reference diameter); 4=strong signs of neointimalhyperplasia, about 50% of reference diameter; and 5=distinct signs ofneointimal hyperplasia (vessel nearly or totally occluded). The CAAS IIfor Research System (Pie Medical, the Netherlands) was used forquantitative coronary analysis.

2. Histology

Hearts were rapidly excised, the coronary system flushed with 0.9%saline and the arteries fixed by perfusion with 4% buffered formalinunder physiological pressure and overnight immersion. Stented coronaryarteries were dissected from the formalin-fixed hearts and immersed inmethyl-methacrylate (Merck, Darmstadt, Germany). Three representativecross sections per stent were separated from the blocks with a rotationmicrotome (Leica RM 2255), polished, and glued on acrylic plasticslides. Final specimens were stained by HE and Masson-Goldner technique.After digitalizing, histomorphometric measurements were taken with theNIH image program (PC version ‘Scion Image,’ Scion Corporation,Maryland, USA). The evaluated parameters were: luminal area, externalelastic lamina (EEL) diameter, maximal neointimal thickness, EEL area,luminal area, and neointimal area.

Histomorphometric variables of the three cross-sectional planes wereaveraged to obtain a mean value per stent. Continuous variables werecompared by ANOVA analysis using the software package SPSS 13.0 forWindows (SPSS Inc. Chicago, Ill.). Data are presented as the mean value±SD.

D. Results

1. Semi-Quantitative Angiographic Coronary Analysis

FIG. 7 illustrates the comparative results of semi-quantitativeangiographic scoring (narrowed compared to reference diameter score >1)of P (TriMaxx Stent on uncoated balloon), DEB (TriMaxx Stent onZotarolimus coated balloon), and DES (ZoMaxx stent on uncoated balloon).An arbitrary scoring system was used in which 0=still oversized, 1=aboutreference diameter, 2=slightly less than reference diameter,3=significantly less than reference diameter, 4=very narrow but notincluded, 5=occluded. As illustrated in FIG. 7, the angiographicstenosis score reveals a reduction of stenosis by the drug eluting stent(DES) and a further improved reduction of stenosis of the Zotarolimuscoated balloon (DEB) after one month.

Table III below summarizes the individual results of thesemiquantitative angiographic scoring.

TABLE III Individual Results of Semi-Quantitative Angiographic ScoringAnimal number Vessel Vessel  # 7 LAD 3-4 CX 0  # 8 LAD* 2 CX 2  # 9 LAD3-4 CX* 0-1 # 10 died shortly after the intervention # 11 LAD 3 CX* 1 #12 LAD 3 CX 1 # 13 LAD 2 CX* 0 # 14 LAD 4 CX occlusion several cm tostent, infarction # 15 LAD 4 CX 1 # 16 LAD* 0-1 CX 1 # 17 LAD 3 CX 2 #18 LAD 2-3 CX 1 # 19 LAD 1 CX* 1 # 20 LAD 3-4 CX* 0 # 21 LAD 4 CX 1-2 #22 LAD 1 CX 3 # 23 LAD* (0)-1 CX 1 # 24 LAD 1 CX 1 # 25 LAD* (0)-1 CX 2# 26 LAD* 1 CX 1 # 27 LAD 1(−2) CX* 0 # 28 LAD* * 1 CX 1 # 29 LAD 3CX* * 0 # 30 LAD 4 CX* 0 # 31 LAD 4 CX* * (0)-1 # 32 LAD 1 CX 2 # 33LAD* * 3(−4) CX 3 # 34 LAD* * 1-2 CX 1 # 35 LAD* * 2 CX (0)-1 # 36 LAD1(−2) CX 1 # 37 LAD 1(−2) CX (0)-1 # 38 died shorty after theintervension # 39 LAD 1-(2) CX* * 1 # 40 LAD* * (0)-1 CX 0 # 41 LAD 3-4CX* * 0-1 # 42 LAD* 1-2 CX 0 # 43 LAD 2-3 CX* * 0-1 # 44 LAD* * 1-2 CX 3# 45 LAD 1-2 CX* * 0 # 46 LAD 3 CX* * 1 # 47 LAD 3 CX 1 # 48 LAD* * 1 CX0-1 # 49 LAD* 1-2 CX 1-2 # 50 LAD 3-4 CX 1 Individual results of semiquantitative angiographic scoring. 0 = still oversized, 1 = aboutreference diameter, 2 = slightly less than reference diameter, 3significantly less than reference diameter, 4 = very narrow but notoccluded, 5 = occluded. Treatment: Placebo (no drug); DES* *; DEB*.

2. Quantitative Coronary Angiography (QCA)

As illustrated in Tables IV, V, and VI below, QCA reveals a reduction oflate lumen loss by the Zotarolimus coated stent and the Zotarolimuscoated balloon. A summary of the late lumen loss as assessed by QCA forthe P, DES and DEB treatments is also shown in FIG. 8.

TABLE IV Results of QCA P DES DEB p stent implantation RFD [mm] 2.30 ±0.37 2.22 ± 0.39 2.33 ± 0.33 0.688 stent diameter [mm] 2.69 ± 0.31 2.66± 0.28 2.64 ± 0.26 0.826 overstretch [—] 1.18 ± 0.15 1.22 ± 0.17 1.14 ±0.11 0.380 control angiography RFD control [mm] 2.38 ± 0.27 2.31 ± 0.232.31 ± 0.30 0.463 MLD control [mm] 1.44 ± 0.58 1.69 ± 0.45 1.77 ± 0.490.126 late lumen loss [mm] 1.26 ± 0.61 0.96 ± 0.36 0.87 ± 0.47 0.028 RFD= reference diameter at baseline [mm], stent diameter [mm], overstretchratio [—], RFD at control [mm], MLD minimal lumen diameter at control[mm], and late lumen loss [mm]. ANOVA analysis.

TABLE V p-Values of QCA p p p P vs DES P vs DEB DES vs DEB RFD [mm]0.460 0.790 0.421 stent diameter [mm] 0.732 0.575 0.853 overstretch [—]0.432 0.329 0.167 RFD control [mm] 0.323 0.351 0.994 MLD control [mm]0.125 0.122 0.978 late lumen loss [mm] 0.084 0.027 0.550

TABLE VI Results of QCA for LAD only only LAD P DES DEB p stentimplantation RFD [mm] 2.17 ± 0.28 2.01 ± 0.33 2.13 ± 0.19 0.409 stentdiameter [mm] 2.59 ± 0.22 2.58 ± 0.24 2.55 ± 0.24 0.898 overstretch [—]1.21 ± 0.18 1.31 ± 0.21 1.20 ± 0.10 0.395 control angiography RFDcontrol [mm] 2.32 ± 0.24 2.15 ± 0.10 2.16 ± 0.24 0.110 MLD control [mm]1.18 ± 0.50 1.42 ± 0.38 1.42 ± 0.38 0.318 late lumen loss [mm] 1.41 ±0.61 1.15 ± 0.37 1.13 ± 0.37 0.328

TABLE VII Results of QCA for CX only only CX P DES DEB p stentimplantation RFD [mm] 2.44 ± 0.40 2.43 ± 0.35 2.53 ± 0.31 0.829 stentdiameter [mm] 2.78 ± 0.36 2.73 ± 0.33 2.73 ± 0.26 0.886 overstretch [—]1.15 ± 0.11 1.13 ± 0.05 1.08 ± 0.09 0.242 control angiography RFDcontrol [mm] 2.45 ± 0.28 2.46 ± 0.23 2.46 ± 0.29 0.997 MLD control [mm]1.69 ± 0.54 1.96 ± 0.35 2.12 ± 0.29 0.235 late lumen loss [mm] 1.11 ±0.57 0.77 ± 0.22 0.60 ± 0.43 0.153

Tables VIII and IX summarize the individual results of QCA for theanimals in the study.

TABLE VIII Individual QCA Results for animals G59/007-G59/028 RFD MLDover- late ID group RFD Stent control control stretch loss G59007cx P2.42 2.71 2.41 1.68 1.12 1.03 G59007lad P 2.31 2.58 2.20 0.82 1.12 1.76G59008cx P 2.14 2.62 2.28 1.50 1.22 1.12 G59008lad DEB 2.13 2.54 1.991.26 1.19 1.28 G59009cx DEB 2.30 2.78 2.21 2.35 1.21 0.43 G59009lad P1.94 2.42 2.16 0.98 1.25 1.44 G59010cx P G59010lad P G59011cx DEB 2.632.89 2.22 2.25 1.10 0.64 G59011lad P 2.19 2.61 1.78 0.85 1.19 1.76G59012cx P 2.80 3.22 2.63 1.88 1.15 1.34 G59012lad P 2.52 2.78 2.67 0.861.10 1.92 G59013cx DEB 2.59 2.76 2.59 1.57 1.07 1.19 G59013lad P 2.242.66 2.39 1.42 1.19 1.24 G59014cx P 2.53 2.93 2.53 0.01 1.16 2.92G59014lad P 1.91 2.58 2.54 0.84 1.35 1.74 G59015cx P 2.40 2.91 2.31 1.841.21 1.07 G59015lad P 1.84 2.91 1.73 0.20 1.58 2.71 G59016cx P 3.07 3.183.11 2.20 1.04 0.98 G59016lad DEB 2.42 2.73 2.29 1.71 1.13 1.02 G59017cxP 1.92 2.72 1.99 1.09 1.42 1.63 G59017lad P 2.57 2.69 2.45 1.59 1.051.10 G59018cx P 2.39 2.52 2.60 1.95 1.05 0.57 G59018lad P 2.23 2.53 2.461.27 1.13 1.26 G59019cx DEB 2.51 2.89 2.65 2.31 1.15 0.58 G59019lad P2.39 2.68 2.21 1.22 1.12 1.46 G59020cx DEB 2.47 2.70 2.35 1.99 1.09 0.71G59020lad P 2.12 2.51 2.16 1.08 1.18 1.43 G59021cx P 2.48 2.48 2.74 1.561.00 0.92 G59021lad P 2.25 2.41 2.51 1.15 1.07 1.26 G59022cx P 2.00 2.382.04 1.08 1.19 1.30 G59022lad P 2.30 2.56 2.48 1.99 1.11 0.57 G59023cx P2.59 2.87 2.42 1.62 1.11 1.25 G59023lad DEB 1.79 2.23 2.13 1.08 1.251.15 G59024cx P 2.76 2.92 2.64 2.68 1.06 0.24 G59024lad P 2.47 2.62 2.452.28 1.06 0.34 G59025cx P 1.85 2.18 2.13 1.38 1.18 0.80 G59025lad DEB2.11 2.35 2.50 1.89 1.11 0.46 G59026cx P 2.72 2.93 2.76 2.18 1.08 0.75G59026lad DEB 2.05 2.82 2.24 1.83 1.38 0.99 G59027cx DEB 2.11 2.16 2.972.36 1.02 −0.20 G59027lad P 2.26 2.48 2.30 1.90 1.10 0.58 G59028cx P2.22 2.54 2.35 1.18 1.14 1.36 G59028lad DES 2.09 2.32 2.24 1.33 1.110.99

TABLE IX Individual QCA Results for animals G59/029-G59/050 RFD MLDover- ID group RFD Stent control control stretch G59029cx DES 2.16 2.532.34 1.71 1.17 G59029lad P 1.50 2.55 2.33 1.18 1.70 G59030cx DEB 3.122.90 2.21 2.02 0.93 G59030lad P 2.57 2.40 2.56 0.69 0.93 G59031cx DES2.72 2.82 2.94 2.35 1.04 G59031lad P 2.10 2.73 2.39 0.89 1.30 G59032cx P2.53 2.61 2.69 0.83 1.03 G59032lad P 1.97 2.36 2.65 2.05 1.20 G59033cx P1.85 2.15 2.05 1.38 1.16 G59033lad DES 1.76 2.40 2.01 0.67 1.36 G59034cxP 2.12 2.29 2.18 1.74 1.08 G59034lad DES 2.15 2.45 2.22 1.87 1.14G59035cx P 2.63 2.84 2.72 2.36 1.08 G59035lad DES 2.43 2.71 2.30 1.351.12 G59036cx P 1.97 2.44 2.24 2.24 1.24 G59036lad P 2.03 2.23 2.57 1.701.10 G59037cx P 2.57 3.33 2.84 2.26 1.30 G59037lad P 2.36 2.66 2.36 1.771.13 G59038cx P G59038lad DEB G59039cx DES 2.00 2.32 2.38 1.45 1.16G59039lad P 2.18 2.60 2.08 1.12 1.19 G59040cx P 3.06 3.16 2.59 2.09 1.03G59040lad DES 1.95 2.77 2.09 1.64 1.42 G59041cx DES 3.03 3.33 2.32 2.211.10 G59041lad P 2.71 3.20 2.34 1.16 1.18 G59042cx P 2.42 2.64 2.55 1.981.09 G59042lad DEB 2.24 2.80 2.22 1.16 1.25 G59043cx DES 2.25 2.53 2.541.63 1.12 G59043lad P 2.51 2.74 2.45 0.36 1.09 G59044cx P 3.59 3.65 2.721.57 1.02 G59044lad DES 2.27 2.96 2.15 1.58 1.30 G59045cx DES 2.52 2.872.37 2.21 1.14 G59045lad P 1.97 2.39 2.16 1.23 1.21 G59046cx DES 2.332.72 2.32 2.17 1.17 G59046lad P 1.99 2.38 2.42 0.89 1.20 G59047cx P 2.673.03 2.37 1.67 1.13 G59047lad P 1.91 2.38 2.24 1.04 1.25 G59048cx P 2.222.76 2.40 1.97 1.24 G59048lad DES 1.45 2.44 2.07 1.53 1.68 G59049cx P2.01 2.80 2.23 1.61 1.39 G59049lad DEB 2.20 2.35 1.73 0.99 1.07 G59050cxP 2.60 3.39 2.12 1.72 1.30 G59050lad P 1.82 3.08 1.83 0.64 1.69

3. Histomorphometry

As represented in Tables X, XI, XII, and XIII, histomorphometry revealeda significant reduction of neointimal formation by the Zotarolimuscoated balloon and Zotarolimus coated stent. A summary of the neointimalarea for the P, DES and DEB treatments is also shown in FIG. 9.

TABLE X Results of Histomorphmetry P DES DEB p n 56 14 14 all vesseldiameter [mm] 3.07 ± 0.16 2.94 ± 0.17 3.07 ± 0.16 0.041 lumen diameter[mm] 1.93 ± 0.48 2.15 ± 0.35 2.20 ± 0.37 0.059 max. neoint. thickn. 0.63± 0.37 0.38 ± 0.21 0.49 ± 0.46 0.055 [mm] vessel area [mm²] 7.44 ± 0.797.05 ± 0.49 7.17 ± 1.08 0.196 luminal area [mm²] 3.12 ± 1.25 3.73 ± 0.984.38 ± 1.37 0.003 neointimal area [mm²] 4.32 ± 1.45 3.32 ± 1.11 2.79 ±1.43 0.001 area stenosis [%] 58% ± 17% 47% ± 13% 38% ± 19% 0.001 injuryscore [—] 1.20 ± 0.86 1.25 ± 0.92 1.16 ± 0.43 0.961 inflammation score1.45 ± 0.94 1.65 ± 0.90 0.75 ± 0.86 0.021 [—] Vessel diameter [mm],lumen diameter [mm], maximal neointimal thickness [mm], vessel area[mm²], area stenosis [%], injury score [—], and inflammation score [—].ANOVA analysis.

TABLE XI Comparison of p-Values of Histomorphometry p p p n P vs DES Pvs DEB DES vs DEB vessel diameter [mm] 0.015 0.943 0.054 lumen diameter[mm] 0.109 0.052 0.717 max. neoint. thickn. 0.018 0.213 0.453 [mm]vessel area [mm²] 0.083 0.286 0.715 luminal area [mm²] 0.096 0.002 0.161neointimal area [mm²] 0.019 0.001 0.281 area stenosis [%] 0.028 0.0010.186 injury score [—] 0.844 0.885 0.752 inflammation score 0.482 0.0130.012 [—]

TABLE XII Results of Histomorphometry for CX only only CX P DES DEB p n28 7 7 vessel diameter [mm] 3.01 ± 0.17 2.85 ± 0.20 3.01 ± 0.17 0.109lumen diameter [mm] 1.93 ± 0.53 2.17 ± 0.17 2.23 ± 0.50 0.426 max.neoint. thickn. 0.53 ± 0.32 0.34 ± 0.11 0.33 ± 0.29 0.254 [mm] vesselarea [mm²] 7.16 ± 0.85 6.74 ± 0.42 6.96 ± 1.14 0.489 luminal area [mm²]3.33 ± 1.32 3.74 ± 0.50 4.24 ± 1.71 0.246 neointimal area [mm²] 3.83 ±1.38 3.00 ± 0.55 2.72 ± 1.56 0.087 area stenosis [%] 53% ± 17% 44% ± 7% 39% ± 22% 0.106 injury score [—] 1.23 ± 0.91 1.14 ± 0.66 1.19 ± 0.230.963 inflammation score 1.48 ± 1.06 1.57 ± 0.63 0.71 ± 0.81 0.157 [—]

TABLE XIII Results of Histomorphometry for LAD only only LAD P DES DEB pn 28 7 7 vessel diameter [mm] 3.12 ± 0.14 3.03 ± 0.07 3.13 ± 0.14 0.258lumen diameter [mm] 1.93 ± 0.41 2.13 ± 0.48 2.17 ± 0.22 0.110 max.neoint. thickn. 0.73 ± 0.39 0.43 ± 0.29 0.64 ± 0.57 0.221 [mm] vesselarea [mm²] 7.73 ± 0.62 7.36 ± 0.32 7.38 ± 1.06 0.285 luminal area [mm²]2.91 ± 1.17 3.72 ± 1.35 4.52 ± 1.06 0.007 neointimal area [mm²] 4.82 ±1.37 3.65 ± 1.46 2.86 ± 1.41 0.004 area stenosis [%] 62% ± 15% 49% ± 18%38% ± 18% 0.002 injury score [—] 1.16 ± 0.83 1.36 ± 1.17 1.14 ± 0.590.856 inflammation score 1.43 ± 0.81 1.73 ± 1.16 0.79 ± 0.98 0.139 [—]

Tables XIV and XV summarize the individual results of histomorphometry.

TABLE XIV Individual Results of Histomorphometry for animalsG59/007-G59/028 ID group vesdia lumdia max thick vesarea lumarea neointarea stenosis injury inflammation G59007cx P 3.10 2.33 0.40 7.70 4.293.41 44.3% 0.50 0.44 G59007lad P 3.17 1.39 1.09 7.89 1.53 6.36 80.6%0.20 0.22 G59008cx P 3.02 1.93 0.66 7.19 2.89 4.30 59.9% 0.90 0.22G59008lad DEB 3.32 1.91 0.63 8.56 4.75 3.81 44.5% 0.86 1.33 G59009cx DEB3.04 2.32 0.48 7.26 3.28 3.98 54.8% 0.90 0.44 G59009lad P 3.32 2.40 0.388.59 4.55 4.04 47.1% 0.20 0.44 G59010cx P G59010lad P G59011cx DEB 2.981.15 0.93 6.92 1.33 5.59 80.8% 1.29 1.00 G59011lad P 3.09 2.14 0.38 6.993.34 3.65 52.3% 0.10 0.56 G59012cx P 3.21 2.02 0.66 7.92 3.24 4.68 59.1%1.00 0.44 G59012lad P 3.19 1.48 0.96 7.93 1.84 6.10 76.8% 2.00 2.33G59013cx DEB 3.11 2.52 0.14 7.57 5.57 2.00 26.4% 1.11 0.22 G59013lad P3.14 1.94 0.68 7.59 2.97 4.63 60.9% 1.30 1.56 G59014cx P 3.12 0.01 1.507.44 0.01 7.43 99.9% 3.00 3.00 G59014lad P 3.41 1.33 1.61 9.65 1.31 8.3586.5% 3.00 3.00 G59015cx P 3.07 1.89 0.73 7.59 2.84 4.74 62.5% 1.30 1.00G59015lad P 3.16 0.75 1.99 8.07 0.44 7.64 94.6% 1.80 2.44 G59016cx P3.28 2.45 0.30 8.30 4.74 3.56 42.9% 0.10 0.22 G59016lad DEB 3.25 2.280.35 8.13 4.41 3.72 45.8% 0.40 0.44 G59017cx P 2.78 1.16 0.88 5.96 1.044.92 82.6% 1.90 1.56 G59017lad P 3.15 1.74 0.71 7.75 2.47 5.28 68.1%0.80 0.78 G59018cx P 2.86 2.12 0.31 6.10 3.37 2.73 44.8% 0.40 0.44G59018lad P 2.78 1.84 0.71 7.45 2.71 4.74 63.6% 1.20 1.11 G59019cx DEB2.66 2.21 0.17 4.51 3.46 1.06 23.4% 1.00 0.22 G59019lad P 3.22 1.94 0.778.01 2.94 5.07 63.3% 0.70 0.89 G59020cx DEB 3.01 2.28 0.27 6.87 4.152.72 39.5% 1.11 0.22 G59020lad P 3.19 2.03 0.65 8.27 3.36 4.91 59.4%0.60 0.78 G59021cx P 2.85 1.96 0.47 6.33 3.10 3.23 51.1% 0.80 0.44G59021lad P 3.01 1.79 0.61 7.19 2.72 4.47 62.2% 0.60 0.67 G59022cx P2.61 1.64 0.48 5.30 2.29 3.01 56.9% 1.10 0.78 G59022lad P 3.01 2.13 0.467.02 3.43 3.59 51.2% 0.50 0.78 G59023cx P 3.11 1.78 0.67 7.48 2.54 4.9566.1% 1.00 1.00 G59023lad DEB 3.09 2.07 0.49 7.65 3.43 4.22 55.2% 1.100.44 G59024cx P 2.97 2.43 0.15 6.45 4.35 2.10 32.6% 0.10 0.11 G59024ladP 3.22 2.67 0.13 8.05 5.71 2.34 29.0% 0.40 0.00 G59025cx P 3.14 1.651.12 7.97 2.21 5.76 72.3% 1.50 1.22 G59025lad DEB 3.15 2.20 0.53 7.775.39 2.38 30.6% 0.50 0.22 G59026cx P 3.12 2.41 0.24 7.63 4.79 2.84 37.2%0.00 0.00 G59026lad DEB 3.07 2.52 0.16 7.62 5.68 1.93 25.4% 1.00 0.00G59027cx DEB 3.14 2.60 0.13 7.71 5.92 1.79 23.2% 0.75 0.33 G59027lad P3.27 2.10 0.55 8.28 3.65 4.62 55.9% 0.80 0.89 G59028cx P 2.75 1.84 0.365.79 2.77 3.01 52.1% 1.60 1.44 G59028lad DES 2.98 2.40 0.24 7.10 4.482.63 37.0% 0.20 0.22

TABLE XV Individual Results of Histomorphometry for animalsG59/029-G59/050 ID group vesdia lumdia max thick vesarea lumarea neointarea stenosis injury inflammation G59029cx DES 2.93 2.01 0.41 6.78 3.293.49 51.4% 0.70 0.89 G59029lad P 2.93 1.71 0.71 6.67 2.27 4.40 66.0%1.70 1.11 G59030cx DEB 3.19 2.51 0.22 7.87 5.95 1.92 24.4% 0.80 2.44G59030lad P 3.12 1.60 0.90 7.68 2.17 5.51 71.8% 0.90 1.00 G59031cx DES3.03 2.46 0.19 7.28 4.66 2.62 36.0% 0.60 2.22 G59031lad P 3.14 1.52 0.987.46 2.00 5.46 73.2% 2.70 2.78 G59032cx P 2.69 1.72 0.58 5.99 2.34 3.6560.9% 2.80 2.56 G59032lad P 3.10 2.40 0.44 7.73 4.52 3.22 41.6% 0.202.67 G59033cx P 3.19 1.79 0.92 8.41 2.65 5.76 68.5% 3.00 3.00 G59033ladDES 3.10 1.16 1.02 7.84 1.11 6.73 85.9% 3.00 3.00 G59034cx P 2.83 2.190.25 6.19 3.67 2.53 40.8% 0.40 2.78 G59034lad DES 3.04 2.37 0.24 7.304.36 2.95 40.3% 1.20 2.56 G59035cx P 3.09 2.58 0.25 7.61 5.73 1.89 24.8%1.20 1.78 G59035lad DES 3.07 2.37 0.38 7.54 4.33 3.20 42.5% 1.00 1.67G59036cx P 3.16 2.39 0.48 7.95 4.65 3.30 41.5% 1.00 1.44 G59036lad P3.01 2.38 0.38 7.19 4.39 2.80 39.0% 0.50 1.22 G59037cx P 3.17 2.73 0.237.76 5.59 2.17 28.0% 0.10 1.00 G59037lad P 3.08 2.32 0.35 7.54 4.26 3.2843.5% 0.70 1.11 G59038cx P G59038lad DEB G59039cx DES 2.89 2.05 0.486.55 3.26 3.28 50.2% 1.90 1.00 G59039lad P 3.13 2.10 0.61 7.80 3.43 4.3656.0% 1.30 2.00 G59040cx P 3.03 2.18 0.32 7.25 3.74 3.51 48.4% 1.70 1.22G59040lad DES 3.12 2.61 0.17 7.66 5.23 2.43 31.7% 0.50 0.33 G59041cx DES2.84 2.26 0.22 6.49 4.05 2.45 37.7% 0.70 1.22 G59041lad P 3.27 2.05 0.618.38 3.59 4.79 57.1% 1.70 2.33 G59042cx P 2.84 2.29 0.25 6.23 3.96 2.2736.4% 0.90 4.00 G59042lad DEB 3.14 2.29 1.88 5.47 5.18 0.29 5.2% 0.800.33 G59043cx DES 2.42 2.16 0.27 6.02 3.74 2.28 37.9% 1.20 1.44G59043lad P 3.00 2.03 0.41 7.12 3.48 3.65 51.2% 1.00 1.78 G59044cx P3.04 1.65 0.80 7.68 2.12 5.55 72.3% 3.00 3.00 G59044lad DES 2.96 2.000.44 7.02 3.31 3.71 52.9% 3.00 3.00 G59045cx DES 2.96 2.24 0.35 6.973.82 3.15 45.2% 1.80 1.56 G59045lad P 3.01 1.97 0.55 7.34 3.12 4.2257.5% 1.50 1.56 G59046cx DES 2.91 1.98 0.44 7.09 3.36 3.73 52.6% 1.902.44 G59046lad P 2.96 1.50 1.00 7.09 1.83 5.27 74.2% 1.90 1.44 G59047cxP 2.98 2.21 0.36 7.21 3.78 3.43 47.5% 2.00 1.78 G59047lad P 2.98 1.560.79 7.20 1.90 5.30 73.6% 1.80 1.22 G59048cx P 3.10 2.63 0.14 7.61 5.152.46 32.3% 0.60 1.00 G59048lad DES 2.96 2.01 0.50 7.08 3.21 3.87 54.7%0.80 1.22 G59049cx P 3.15 1.75 0.83 7.99 2.45 5.54 69.3% 1.60 2.00G59049lad DEB 2.87 1.90 0.44 6.46 2.80 3.66 56.7% 2.30 2.78 G59050cx P3.11 1.99 0.58 7.46 2.94 4.51 60.5% 1.70 2.22 G59050lad P 3.35 1.41 1.128.45 1.63 6.82 80.7% 2.90 2.44

4. Conclusion

The studies indicate show a significant reduction of neointimalformation by the Zotarolimus coated stent and coated balloon. Theefficacy in reduction of neotintimal formation by the Zotarolimus coatedballoon is comparable to the Zotarolimus coated stent, and in someinstances the zotarolimus coated balloon has greater efficacy than thezotarolimus coated stent.

As will be recognized by those of ordinary skill, the examples can beadapted to address situations for which it is desired to delivermultiple stents, e.g., “kissing” stents or overlapping stents.

What is claimed is:
 1. A system for treating vascular diseasecomprising: a balloon having an outer surface for temporary contact witha vessel wall when in an expanded state; a coating disposed on at leasta portion of the outer surface, the coating including an initial amountof a cytostatic agent selected from the group consisting of Zotarolimus(ABT578), everolimus, pimecrolimus, and a combination thereof, thecoating being capable of maintaining a therapeutically effective amountof the cytostatic agent on the outer surface for delivery to a vesselwall, and further wherein between about 4.9% to about 23% of the initialamount of the cytostatic agent on the outer surface remains disposed onthe outer surface after delivery of the therapeutically effective amountof the cytostatic agent to the vessel wall; and optionally, a stentdisposed on the balloon.
 2. The system of claim 1, wherein thecytostatic agent is zotarolimus.
 3. The system of claim 2, wherein thezotarolimus is disposed on the outer surface at a concentration of fromabout 3.7 μg/mm² to about 7.0 μg/mm².
 4. The system of claim 2, whereinthe coating further comprises ethanol, Iopromide and acetone.
 5. Thesystem of claim 2, wherein the cytostatic agent is zotarolimus and thetherapeutically effective amount of zotarolimus is effective to maintainat least about 35.7% of a vessel lumen diameter after delivery of thetherapeutically effective amount of zotarolimus.
 6. The system of claim1, wherein the coating further comprises binders, polymers, solvents, orcombinations thereof.
 7. The system of claim 6, wherein the binder isselected from the group consisting of complex sugars, starches,collagens, and polymeric materials.
 8. The system of claim 1, whereinthe stent is crimped onto the balloon.
 9. The system of claim 1, whereinthe stent is a self-expanding stent.
 10. The system of claim 1, whereinthe coating includes an additional beneficial agent.
 11. The system ofclaim 1, wherein the therapeutically effective amount of the cytostaticagent is effective to reduce neointimal formation after delivery of thecytostatic agent to the vessel wall.
 12. The system of claim 1, whereinthe therapeutically effective amount of the cytostatic agent isdelivered within about 60 seconds of contact between the balloon in anexpanded condition and the vessel wall.